Continuous manufacturing: ICH Q13

Historically, most active pharmaceutical ingredients (APIs) and drug products have been manufactured via batch-based processes. These multi-step, multi-vessel, lengthy procedures, frequently involving discrete, isolated intermediates are often scale-dependent. Process knowledge accrued at small scale often needs to be re-learned as the method is scaled up. However, recent advances in both manufacturing technology and supporting process analytical technology (PAT) have encouraged the pharmaceutical industry to contemplate replacing batch manufacturing with faster, more efficient continuous manufacturing processes. Here, the ‘product’ moves through the various manufacturing stages in a continuous, automated fashion with minimal intervention or stoppage of the process.¹ Although process throughput is typically less than in the standard batch process, continuous manufacturing can operate 24/7 and achieve a similar capacity without the need for scale up by operating for longer time periods.

Regulatory agencies are taking proactive steps to enable the implementation of continuous manufacturing; they see it as a means “to improve product quality and address many of the underlying causes of drug shortages and recalls”.² However, progress remains frustratingly slow, with only a limited number of continuously manufactured products being approved on a year-on-year basis.¹ One reason for this is that continuous manufacturing challenges many of the basic precepts of quality management, particularly what constitutes a batch and how an organisation controls the quality of the batch, especially during process start up and shut down. For example, in batch manufacturing, a specified amount (or batch) of an API or drug product is intrinsically defined by the size of the equipment (or equipment train) that produced it. By contrast, in continuous manufacturing a quantity (or batch) can be defined by a pre-defined timed interval, the amount of API or drug product produced, or the amount of raw input material used. These tracing methodologies permit the manufacturer to isolate a smaller amount of substandard material during start up or shut down or in the event of a process failure, which in turn leads to reduced waste and minimised drug shortages.

ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products seeks to provide a harmonised approach to support this important initiative. Some issues that need to be resolved relate to fundamental definitions requiring “further clarification or explanation in the regulatory context, for example, definition of continuous manufacturing, start up/shut down, state of control, process validation and continuous process verification”. This should lead to improved interaction between different international regulatory agencies. In addition, a shared awareness of the scientific methodologies employed will ensure reproducible “science- and risk-based implementation and regulatory assessment” of continuous manufacturing throughout the different ICH regions. This is important because the underpinning scientific methodologies used in continuous manufacturing may be intrinsically different from those utilised in batch-based processes, eg, system dynamics, testing frequency, identification and removal of non-compliant product, product traceability, process models and advanced PAT controls. Although the scientific methodologies enshrined in the ICH Q13 guideline are intended to cover only small organic molecules and therapeutic proteins, these approaches may also be applicable to other larger biological molecules. The harmonised approaches will cover both new “marketing applications and post-approval changes, site implementation and pharmaceutical quality systems”.

ICH Q13 aims to harmonise global regulations for continuous manufacturing; the current process makes it significantly more challenging when trying to address country specific versus global requirements for any new product.¹ Currently, the implementation of continuous manufacturing for any given product is “driven by the speed of the slowest global regulatory approval, not the fastest”. In addition, this regulatory non-alignment was recently cited as one of the major impediments to successfully implementing continuous manufacturing.³

References

1. Toro JL. Continuous Manufacturing and its Regulatory Challenge. Contract Pharma, 16 September 2019. https://www.contractpharma.com/issues/2019-09-01/view_fda-watch/continuous-manufacturing-and-its-regulatory-challenge/ [Accessed on 02 August 2020].
2. Lee L. Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing. 17 May 2017. https://www.fda.gov/drugs/news-events-human-drugs/modernizing-way-drugs-are-made-transition-continuous-manufacturing [Accessed on 02 August 2020].
3. Elder DP, Tindall S, Savla R. Continuous manufacturing: regulatory and quality assurance challenges. Eur. Pharm. Rev., 22(4), 60-64, 2017.